Glutamic acid acts as a neurotransmitter in the mammalian central nervous system (Mayer M. L. and Westbrook G. L., Prog. Neurobiol., 28 (1987) 197-276). By the recent studies, importance of glutamic acid in the higher order cranial nerve function has been revealed. Glutamic acid is released from the nerve ending and regulates activity of nerve cells or release of a neurotransmitter, via glutamate receptors which are present in the postsynaptic membrane or nerve ending. Based on various pharmacological and physiological studies, glutamate receptors are currently classified roughly into two categories. One of them is ionotropic receptor and the other is metabotropic receptor (Hollmann M and Heinemann S., Annu. Rev. Neurosci., 17 (1994) 31-108).
Based on the molecular biological studies, it has been reported that the metabotropic glutamate receptor (to be referred sometimes to as mGluR hereinafter) exists so far in at least eight different subtypes of from mGluR 1 to mGluR 8. The mGluR is classified into a group of receptors (group I: mGluR 1 and mGluR 5) which accelerate production of inositol triphosphate (IP3) and incorporation of calcium ions into cells, by coupling with phospholipase C via G protein, and other groups of receptors (group II: mGluR 2 and mGluR 3, group III: mGluR 4, mGluR 6, mGluR 7 and mGluR 8) which inhibit production of cAMP by coupling with Gi protein. These receptors show different intracerebral distributions from one another, for example, mGluR 6 does not exist in the brain but exists only on the retina, so that it is considered that each receptor is taking each own different physiological role (Nakanishi S., Neuron, 13 (1995) 1031-1037).
Compounds which are selective for the mGluR in comparison with the ionotropic receptor have so far been reported (Hayashi Y. et al., Br. J. Pharmacol., 107 (1992) 539-543; Hayashi Y. et al., J. Neurosci., 14 (1995) 3370-3377), and relationships between the mGluR and various morbid states of diseases have been reported as the following cases (1) to (6), based on the studies carried out using these compounds.
(1) Epilepsy is induced by the administration of an mGluR agonist (1S,3R)-1-aminocyclopentane-1,3-dicarboxylic acid (to be referred to as (1S,3R)-ACPD hereinafter) (Tizzano J. P. et al., Neurosci. Lett., 162 (1993) 12-16; McDonald J. W. et al., J. Neurosci., 13 (1993) 4445-4455). In addition, the efficacy of (S)-4-carboxy-3-hydroxyphenylglycine (to be referred to as (S)-CHPG hereinafter), which is an antagonist of mGluR 1 and also an agonist of mGluR 2, in various epilepsy models has been reported (Dalby, N. O. & Thomsen, C. J., J. Pharmacol. Exp. Ther., 276 (1996) 516-522).
(2) Participation of mGluR in the transmission of pain sensation into spinal posterior horn nerve cells has been confirmed by electro-physiological tests (Young, M. R. et al., Neuropharmacology, 33 (1994) 141-144; ibid., 34 (1995) 1033-1041). In addition, it has been reported that the (S)-CHPG has an action to delay avoiding reaction of thermal and mechanical pain sensation stimulation (Young, M. R. et al., Br. J. Pharmacol., 114 (1995) 316P).
(3) It has been reported that when the (1S,3R)-ACPD or an mGluR agonist (RS)-3,5-dihydroxyphenylglycine (to be referred to as 3,5-DHPG hereinafter) is administered in a trace amount or systemically to the cerebral parenchyma of mouse or rat, it causes nerve cell death accompanied by spasm (Lipartit, M. et al., Life Sci., 52 (1993) PL 85-90; McDonald, J. W. et al., J. Neurosci., 13 (1993) 4445-4455; Tizzano, J. P. et al., Neuropharmacology, 34 (1995) 1063-3067). It is considered that this is a result of the activation of mGluR 1 and mGluR 5.
(4) It is well known that chronic administration of benzodiazepine forms its dependency. It has been reported that metabolic turnover of inositol-phospholipid increases by (1S,3R)-ACPD via mGluR, on the second day and third day after 7 days of continuous administration of benzodiazepine, and it has been suggested that mGluR is taking a role in the expression of benzodiazepine withdrawal syndrome (Mortensen, M. et al., J. Pharmacol. Exp. Ther., 274 (1995) 155-163).
(5) It has been reported that N-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-induced substantia nigra dopamine nerve cell death is inhibited by the ventricular administration of a mGluR group I antagonist 1-aminoindane-1,5-dicarboxylic acid (Aguirre, J. A. et al., Neuroreport. 12 (2001) 2615-2617).
(6) It has been reported that an antagonist of mGluR 1 inhibits protein extravasation outside of dural blood vessels caused by an electric stimulus of trigeminal ganglion (WO 01/32632).
That is, the above reports show that compounds which act upon mGluR 1 are useful in epilepsy, pain, nerve cell death inhibition, benzodiazepine withdrawal syndrome and migraine.
Also, since the efficacy of a mGluR 1 antagonist has been confirmed in a rat cerebral infarction model, it is considered that the mGluR 1 antagonist is useful as a preventive or therapeutic agent for cerebral infarction (Patent Reference 1).
In addition, since it has been confirmed that a mGluR 1 antagonist improves reduction of pain threshold in neuropathic pain model, it is also useful as an agent for treating neuropathic pains such as a pain after shingles, a pain accompanied by diabetic neuropathy, a carcinomatous pain, a postoperative chronic pain and the like (Patent Reference 2).
As compounds having mGluR 1 antagonism, thiazolobenzimidazole derivatives are disclosed in the aforementioned Patent References 1,2 and 3 and Patent Reference 4.
However, the thiazolobenzimidazole derivatives disclosed in the aforementioned Patent References 1, 3 and 4 are compounds which were found aimed at cerebral infarction as the principal indication whose main administration route is parenteral administration.
In addition, it is reported in the Patent Reference 2 that thiazolobenzimidazole derivatives in which the benzene ring moiety of thiazolobenzimidazole ring is substituted with substituted or unsubstituted amino group show a neuropathic pain therapeutic effect by oral administration.
[Patent Reference 1]
PCT International Publication Pamphlet WO 99/44639
[Patent Reference 2]
PCT International Publication Pamphlet WO 01/08705
[Patent Reference 3]
PCT International Publication Pamphlet WO 00/59913
[Patent Reference 4]
JP-A-2000-351782
Problems that the Invention is to Solve
The object of the invention is to provide clinically useful novel thiazolobenzimidazole derivatives and a salt thereof, as metabotropic glutamate receptor antagonists having excellent oral activity.
Also, though the compounds of the aforementioned Patent Reference 2 have an oral activity, they also have a carcinogenic action, because it has been confirmed by this firm's studies that they have gene mutagenicity. It is considered that this gene mutagenicity is expressed by a structural characteristic in that they have an aniline amino group, so that compounds having an aniline amino group have a disadvantage in that they cannot be used in clinical tests as a medicament even in case that they have an oral activity.
The present inventors have conducted intensive studies with the aim of solving the aforementioned problems, and accomplished the invention by finding that the aminomethyl-substituted thiazolobenzimidazole derivatives of the invention are compounds which have a strong oral activity as a metabotropic glutamate receptor antagonist and are clinically useful because of no mutagenicity.
In this connection, the compounds of the invention are compounds which are not illustratively disclosed in the aforementioned Patent References 1 and 3, in terms that they have an oxygen-containing saturated hetero ring, a sulfur-containing saturated hetero ring or the like, or an aminomethyl group substituted with an alkyl substituted with such a saturated hetero ring, as a substituent group on the benzene ring moiety of thiazolobenzimidazole ring.
Accordingly, the invention relates to aminomethyl-substituted thiazolobenzimidazole derivatives represented by the following general formula (I) or a salt thereof and a medicament which uses the same as the active ingredient.
Illustratively, it relates to an aminomethyl-substituted thiazolobenzimidazole derivative represented by the following general formula (I) or a salt thereof
(wherein signs in the formula mean as follows;    R1: an oxygen-containing saturated hetero ring- which may be substituted, a sulfur-containing saturated hetero ring- which may be substituted, a cycloalkyl which may be substituted, —O—R6 or —S—R7,    Alk1: a lower alkylene,    m: 0 or 1,    Alk2: a lower alkylene which may be substituted with oxo group,    n: 0 or 1,    X: a bond, O, S or NR5,    R3: H, a lower alkyl, a halogeno-lower alkyl, a lower alkenyl, a lower alkynyl, a cycloalkyl which may be substituted, cyano or a saturated hetero ring-, and R2, R4, R5, R6 and R7: the same or different from each other and each represents H or lower alkyl, with the proviso that R3 does not represent a lower alkyl or a halogeno-lower alkyl when X is a bond and n is 1, and that R4 represents a group other than methyl when m is 1, R1 is OH or a methoxy and Alk1 is a C1-3 alkylene, and further 1) when X is a bond, n is 1 and R3 is H, or 2) when X is a bond, n is 0 and R3 is a cycloalkyl).
Preferred is aminomethyl-substituted thiazolobenzimidazole derivatives or a salt thereof, in which R1 in the general formula (I) is an oxygen-containing saturated hetero ring- which may be substituted, and R3 is a lower alkyl or a saturated hetero ring-;
more preferred is N-methyl-N-neopentyl-6-[(oxetan-3-ylamino)methyl]thiazolo[3,2-a]benzimidazole-2-carboxamide; 6-{[(1,3-dioxolan-2-ylmethyl)amino]methyl}-N-methyl-N-neopentylthiazolo[3,2-a]benzimidazole-2-carboxamide; or N-neopentyl-6-({[tetrahydro-2H-pyran-4-yl)methyl]amino)methyl)thiazolo[3,2-a]benzimidazole-2-carboxamide or a salt thereof.
The present invention further relates to a medicament which comprises the aforementioned aminomethyl-substituted thiazolobenzimidazole derivative represented by general formula (I) or a salt thereof as the active ingredient, preferably a mGluR 1 receptor antagonist.
More preferably, it is a pharmaceutical composition having a mGluR 1 receptor antagonism, which comprises a mGluR 1 receptor binding-inhibitory amount of the aforementioned aminomethyl-substituted thiazolobenzimidazole derivative or a salt thereof.
Further preferably, it relates to a therapeutic agent for a disease in which activation of mGluR 1 receptor is concerned, which comprises the aforementioned aminomethyl-substituted thiazolobenzimidazole derivative or a salt thereof as the active ingredient, illustratively a therapeutic agent for a neuropathic pain.
Best Mode for Carrying Out the Invention
The following further describes the compound of the invention.
In the definition of general formulae as used herein, unless otherwise noted, the term “lower” means a straight or branched carbon chain having from 1 to 6 carbon atoms.
The “lower alkyl” is a C1-6 alkyl, preferably a straight or branched C1-4 alkyl such as methyl, ethyl, propyl, isopropyl, t-butyl or the like, more preferably a C1-3 alkyl.
The “lower alkylene” is a C1-6 alkylene, preferably straight or branched C1-4 alkylene (e.g, methylene, ethylene, methylmethylene, trimethylene, propylene, ethylethylene, tetrabutylene or the like), further preferably a C1-3 alkylene.
The “lower alkylene substituted with oxo group” means a group in which an optional carbon atom of a straight or branched C2-6 alkylene among the aforementioned lower alkylene groups is substituted with oxo group, and preferred is —CH2—C(O)—, —C(O)—CH2—, —CH2—C(O)—CH2—, —(CH2)2—C(O)— or —C(O)—(CH2)2—.
The “lower alkenyl” is a C2-6 alkenyl, preferably straight or branched C2-4 alkenyl (e.g., vinyl, propenyl, butenyl or the like), more preferably a C2-3 alkenyl.
The “lower alkynyl” is a C2-6 alkynyl, preferably straight or branched C2-4 alkynyl (e.g., acetynyl, propynyl, butynyl or the like), more preferably a C2-3 alkynyl.
The “halogen” means a halogen atom, for example, it means fluorine, chlorine, bromine or iodine atom.
The “halogeno-lower alkyl” means a group in which optional one or more hydrogen atoms of the aforementioned lower alkyl are substituted with the aforementioned halogen atoms, and trifluoromethyl is desirable.
The “cycloalkyl” means a 3- to 8-membered cycloalkyl, and preferred is cyclopropyl, cyclopentyl, cyclohexyl, cycloheptyl or the like.
The “saturated hetero ring” means a 3- to 8-membered saturated hetero ring containing from 1 to 4 hetero atoms selected from nitrogen atom, oxygen atom and sulfur atom, and its examples include pyrrolidine, piperidine, piperazine, homopiperazine, imidazolidine, morpholine, thiomorpholino, oxirane, oxetane, thietane, tetrahydrofuran, tetrahydropyran, [1,3]dioxolan, [1,4]dioxane, tetrahydrothiophene, [1,4]dithian, hexahydroazepin, hexahydro-pyrrolo[2,1-c][1,4]oxazine and the like.
Preferred is a 5-membered oxygen-containing saturated hetero ring or sulfur-containing saturated hetero ring.
The “oxygen-containing saturated hetero ring” means a saturated hetero ring necessarily containing oxygen atom as a hetero atom in the ring among the aforementioned hetero rings. That is, it means a 3- to 8-membered saturated hetero ring which may contain 1 or 2 nitrogen atom or sulfur atom, in addition to 1 to 3 oxygen atoms. Preferred is a 4- to 6-membered oxygen-containing saturated hetero ring, and more preferred is oxetane, tetrahydrofuran, 1,3-dioxolan tetrahydropyran, or morpholine.
The “sulfur-containing saturated hetero ring” means a saturated hetero ring necessarily containing sulfur atom as a hetero atom in the ring among the aforementioned hetero rings. That is, it means a 3- to 8-membered saturated hetero ring which may contain 1 or 2 nitrogen atom or oxygen atom, in addition to 1 to 3 sulfur atoms. Preferred is a 4- to 6-membered saturated hetero ring, and more preferred is thietane, 1,3-dithiolan, tetrahydrothiophene, thiazolidine or thiomorpholine.
The oxygen-containing saturated hetero ring which may be substituted, the sulfur-containing saturated hetero ring which may be substituted and the cycloalkyl which may be substituted may have 1 to 3 substituent groups on optional carbon atoms or hetero atoms on the ring.
The substituent group means a usual substituent group of a group to be substituted commonly used in said field, and its most desirable examples include a halogen, cyano, a halogeno-lower alkyl, a lower alkyl, OH, a lower alkyl-O—, oxo, a lower alkyl-C(O)—, carboxyl, a lower alkyl-O—C(O)—, a lower alkyl-O-lower alkyl-, nitro, amino which may be substituted with 1 or 2 lower alkyl groups, and the like.
Preferred are a lower alkyl and a lower alkyl-O—.
Depending on the kind of groups, the compound of the invention exists in optical isomer forms (optically active substances, diastereomers and the like). In addition, compounds having amido bond or double bond are included in the compound of the invention, so that tautomers and geometrical isomers also exist. These isomers in the isolated or mixed form are included in the invention.
The compound of the invention forms a salt with an acid or a base. Examples of the salt with an acid include acid addition salts with in organic acids such as mineral acids (e.g., hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, nitric acid, phosphoric acid and the like) or with organic acids (e.g., formic acid, acetic acid, propionic acid, oxalic acid, malonic acid, succinic acid, fumaric acid, maleic acid, lactic acid, malic acid, citric acid, tartaric acid, carbonic acid, picric acid, methanesulfonic acid, ethanesulfonic acid, glutamic acid and the like).
Examples of the salt with a base include salts with inorganic bases such as sodium, potassium, magnesium, calcium, aluminum and the like, with organic bases such as methylamine, ethylamine, meglumine, ethanolamine and the like, or with basic amino acids such as lysine, arginine, ornithine and the like, as well as an ammonium salt. In addition, the compound of the invention can form hydrates, solvates such as with ethanol and the like and polymorphism.
In addition, a pharmacologically acceptable prodrug is included in the compound of the invention. Examples of the group which forms the pharmacologically acceptable prodrug of the compound of the invention include the groups described in Prog. Med., 5: 2157-2161 (1985) and the groups described in “Development of Medicaments” vol. 7, Molecular Designing, pp. 163-198, published in 1990 by Hirokawa Shoten. Illustratively, it is a group which can be converted into the primary amine, secondary amine, OH, COOH or the like of the invention by hydrolysis or solvolysis or under a physiological condition, and its examples in the case of a prodrug of OH group include —OCO— (lower alkylene which may be substituted) —COOR (R represents H or a lower alkyl, the same shall apply hereinafter), —OCO— (lower alkenylene which may be substituted) —COOR, —OCO— (aryl which may be substituted), —OCO— (lower alkylene) —O— (lower alkylene) —COOR, —OCO—COR, —OCOO— (a lower alkyl which may have be substituted), —OSO2— (a lower alkylene which be substituted) —COOR, —O-phthalidyl, 5-methyl-1,3-dioxolen-2-on-4-yl-methyloxy or the like.
Also, it is possible to use the compound of the invention in combination with an analgesic, an antiviral agent, a diabetes treating agent or the like.
Examples of the analgesic include pirin, non-pirin and the like non-steroidal anti-inflammatory drugs (NSAID), central analgesics (pentazocine and the like) and opioid analgesics (morphine and the like).
Examples of the diabetes treating agent include sulfonylurea agents (tolbutamide and the like), α-glucosidase inhibitors (acarbose and the like), thiazolidine-dione agents (triglytazone and the like) and biguanide agents (metformin and the like).
Examples of the antiviral agent include acyclovir, paracyclovir, famciclovir and the like.
In addition to the above, the following can be exemplified as agents which can be jointly used.
Carbamazepine and the like anticonvulsants, imiplamine and the like antidepressants, mexiletine and the like anti-arrhythmic drugs, lidocaine and the like local anesthetics, xanthine preparations (caffeine and the like), ergotamine agents and calcium antagonists (romelizin hydrochloride and the like).
Production Methods
In this specification, the signs used in the general production methods, reference examples, examples and tables have the following meanings.
DMF: dimethylformamide, DMSO: dimethyl sulfoxide, THF: tetrahydrofuran
Production Method 1: Reductive Amination
(In the formula, Ra means OH, or a lower alkyl-O—, or N(R4) (Alk2)n—X—R3. Other signs are as defined in the foregoing. The same shall apply hereinafter.)
From (II) to (I-a) is a usual reductive amination reaction. That is, the desired (I-a) can be obtained by allowing an aldehyde (II) and a corresponding amine to undergo the reaction using a reducing agent (e.g., sodium triacetoxyborohydride, sodium cyanoborohydride, sodium borohydride or the like) in a solvent (e.g., methylene chloride, 1,2-dichloroethane, chloroform, THF, methanol, ethanol or the like), if necessary in the presence of an acid catalyst (e.g., acetic acid, hydrochloric acid or the like) or Lewis acid (e.g., titanium tetraisopropoxide or the like). The (I-a) can also be synthesized by allowing the (II) and a corresponding amine to undergo the reaction in an inert solvent (e.g., toluene, benzene or the like) at a temperature of from 10° C. to 150° C. under a dehydration reaction condition using a dehydrating agent (e.g., Molecular Sieves or the like) or Dean-Stark filtration equipment for dewatering as occasion demands, thereby forming an imine, and then treating it with a reducing agent (e.g., sodium borohydride or the like) in a solvent (e.g., methanol, ethanol or the like). In addition, the (I-a) can also be synthesized by using a metal catalyst (e.g., palladium or the like) instead of the aforementioned reducing agent under a catalytic reduction condition, illustratively under an atmosphere of hydrogen.
Production Method 2: Alkylation
(In the formula, A means a leaving group such as a halogen, sulfonyloxy group or the like.)
From (III) to (I-a) is a usual N-alkylation reaction. That is, the desired (I-a) can be obtained by allowing (III) and a corresponding amine to undergo the reaction at from ice-cooling to 200° C. in an inert solvent (e.g., DMF, acetonitrile, chloroform, THF or the like) in the presence of a base (e.g., potassium carbonate, sodium bicarbonate, triethylamine, ethyl diisopropylamine or the like). The corresponding amine may be used in excess amount in this reaction.
Production Method 3: Amidation
(In the formula, B means OH or N(R2′) (Alk1)m-R1, wherein R2′ means H, a lower alkyl which may be substituted, or a general amino group protecting group.)
From (IV) to (I-b) is a usual amidation reaction. That is, the desired (I-b) can be obtained by activating a carboxylic acid (IV) with a condensing agent (e.g., dicyclohexylcarbodiimide, 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide, diphenylphosphoryltriazide, 1,1′-carbonyl-1H-imidazole, 1-hydroxybenzotriazole or the like) in an inert solvent (e.g., DMF, THF, 1,2-dichloroethane, chloroform or the like), and then allowing this active compound to react with a corresponding amine. For activating the carboxylic acid, an acid chloride method in which thionyl chloride, oxalyl chloride or the like is used, a mixed acid anhydride method, or an active phosphoric acid ester method in which phosphorus oxychloride or the like is used can also be used.
Production Method 4: N-Alkylation

From (I-c) to (I) is a usual N-alkylation reaction. That is, the desired (I) can be obtained by allowing to react with a corresponding alkylating agent (e.g., alkyl halide, sulfonic acid alkyl ester or the like) under from ice-cooling to heating in an inert solvent (e.g., DMF, DMSO, THF, acetone, acetonitrile or the like) using a base (e.g., potassium carbonate, cesium carbonate, sodium hydride, potassium hydroxide or the like).
General protecting groups and the like of hydroxyl group, amino group, ester group and the lie are described in detail in PROTECTIVE GROUPS IN ORGANIC SYNTHESIS, edited by THEODORA W. GREENE and PETER G. M. WUTS, and the disclosure of this reference is incorporated in this specification.
In this connection, the aforementioned production methods are not restricted by the substituent groups of the formulae and can be broadly applied even to a case in which a compound of the invention has similar substituent groups or a case in which a reaction substrate and a reactant have opposite relation.
The compound of the invention produced in this manner is isolated and purified in its free form or as a salt thereof.
The isolation and purification are carried out by employing usual chemical operations such as extraction, concentration, evaporation, crystallization, filtration, recrystallization, various types of chromatography and the like.
Various isomers can be separated by selecting appropriate material compounds or making use of the difference in physiological properties among isomers. For example, optical isomers can be separated into stereochemically pure isomers by selecting an appropriate material or by a method for the optical resolution of racemic compounds (e.g., a method in which they are converted into diastereomer salts with a general optically active base and then subjected to optical resolution).
A pharmaceutical preparation which contains one or more of the compounds of the invention or salts thereof as the active ingredient is prepared using carriers, fillers and other additives generally used in the preparation of medicaments.
The carriers and fillers for pharmaceutical preparation use may be either solid or liquid, and their examples include lactose, magnesium stearate, starch, talc, gelatin, agar, pectin, acacia, olive oil, sesame oil, cacao butter, ethylene glycol and other generally used substances.
It may be administered either by oral administration through tablets, pills, capsules, granules, powders, solutions or the like, or by parenteral administration through injections such as for intravenous injection, intramuscular injection or the like, suppositories, percutaneous preparations and the like. Its dose is optionally decided by taking into consideration conditions of each case such as symptoms, age, sex and the like of the patient to be treated, but, usually, it is orally administered within the range of from 1 to 1,000 mg, preferably from 50 to 200 mg, per day per adult by dividing the daily dose into 1 to several doses per day or intravenously injected within the range of from 1 to 500 mg per day per adult by dividing the daily dose into 1 to several doses per day, or continuously and intravenously injected within the range of from 1 to 24 hours per day. As a matter of course, since the dose varies under various conditions as described in the foregoing, a smaller dose than the above range may be sufficient enough in some cases.
As the solid composition for use in the oral administration according to the invention, tablets, powders, granules and the like are used. In such a solid composition, one or more active substances are mixed with at least one inert diluent such as lactose, mannitol, glucose, hydroxypropylcellulose, microcrystalline cellulose, starch, polyvinyl pyrrolidone or aluminum magnesium metasilicate. In accordance with the usual way, the composition may contain other additives than the inert diluent, which include a lubricant such as magnesium stearate, a disintegrating agent such as starch or calcium cellulose glycolate, a stabilizing agent such as lactose and a solubilization assisting agent such as glutamic acid or aspartic acid. As occasion demands, tablets or pills may be coated with a film of a gastric or enteric substance such as sucrose, gelatin, hydroxypropylcellulose, hydroxypropylmethylcellulose phthalate or the like.
The liquid composition for oral administration use includes pharmaceutically acceptable emulsions, solutions, suspensions, syrups, elixirs and the like and contains a generally used inert diluent such as purified water or ethanol. In addition to the inert diluent, this composition may also contain auxiliary agents such as a moistening agent and a suspending agent, as well as a sweetener, a flavor, an aromatic and an antiseptic.
The injections for parenteral administration use include aseptic aqueous or non-aqueous solutions, suspensions and emulsions. Examples of the diluent for use in the aqueous solutions and suspensions include distilled water for injection and physiological saline. Examples of the diluent for use in the non-aqueous solutions and suspensions include propylene glycol, polyethylene glycol, plant oils (e.g., olive oil), alcohols (e.g., ethanol) and polysorbate 80. Such a composition may further contain auxiliary agents such as an antiseptic, a moistening agent, an emulsifying agent, a dispersing agent, a stabilizing agent (e.g., lactose) and a solubilization assisting agent (e.g., glutamic acid or aspartic acid). They are sterilized by, for example, filtration through a bacteria retaining filter, blending of a germicide or irradiation. Alternatively, they may be used by firstly making into sterile solid compositions and dissolving them in sterile water or a sterile solvent for injection prior to their use.